C2 substituted taxanes

ABSTRACT

Taxane derivatives having alternative C2 substituents.

REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part application of U.S.Ser. No. 08/034,247 filed Mar. 22, 1993 which is a continuation-in-partof U.S. Ser. No. 07/949,107, filed Sep. 22, 1992, which is acontinuation-in-part application of U.S. Ser. No. 07/863,849, filed Apr.6, 1992, now abandoned, which is a continuation-in-part application ofU.S. Ser. No. 07/862,955, filed Apr. 3, 1992, now abandoned, which is acontinuation-in-part of U.S. Ser. No. 07/763,805, filed Sep. 23, 1991,now abandoned. This application is also a continuation-in-part of U.S.Ser. No. 08/010,798, filed Jan. 29, 1993.

BACKGROUND OF THE INVENTION

[0002] The present invention is directed to novel taxanes which haveutility as antileukemia and antitumor agents.

[0003] The taxane family of terpenes, of which taxol is a member, hasattracted considerable interest in both the biological and chemicalarts. Taxol is a promising cancer chemotherapeutic agent with a broadspectrum of antileukemic and tumor-inhibiting activity. Taxol has a 2′R,3′S configuration and the following structural formula:

[0004] wherein Ac is acetyl. Because of this promising activity, taxolis currently undergoing clinical trials in both France and the UnitedStates.

[0005] Colin et al. reported in U.S. Pat. No. 4,814,470 that taxolderivatives having structural formula (2) below, have an activitysignificantly greater than that of taxol (1).

[0006] R′ represents hydrogen or acetyl and one of R″ and R′″ representshydroxy and the other represents tert-butoxy-carbonylamino and theirstereoisomeric forms, and mixtures thereof. The compound of formula (2)in which R′ is hydroxy, R′″ is tert-butoxycarbonylamino having the 2′R,3′S configuration is commonly referred to as taxotere.

[0007] Although taxol and taxotere are promising chemotherapeuticagents, they are not universally effective. Accordingly, a need remainsfor additional chemotherapeutic agents.

SUMMARY OF THE INVENTION

[0008] Among the objects of the present invention, therefore, is theprovision of novel taxane derivatives which are valuable antileukemiaand antitumor agents.

[0009] Briefly, therefore, the present invention is directed to C2taxane derivatives. In a preferred embodiment, the taxane derivative hasa tricyclic or tetracyclic core and corresponds to the formula:

[0010] wherein

[0011] X₁ is —OX₆, —SX₇, or —NX₈X₉;

[0012] X₂ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

[0013] X₃ and X₄ are independently hydrogen, alkyl, alkenyl, alkynyl,aryl, or heteroaryl;

[0014] X₅ is —COX₁₀, —COOX₁₀, —COSX₁₀, —CONX₈X₁₀, or —SO₂X₁₁;

[0015] X₆ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,hydroxy protecting group, or a functional group which increases thewater solubility of the taxane derivative;

[0016] X₇ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydrylprotecting group;

[0017] X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, orheterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;

[0018] X₉ is an amino protecting group;

[0019] X₁₀ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, orheterosubstituted alkyl, alkenyl alkynyl, aryl or heteroaryl;

[0020] X₁₁ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OX₁₀, or—NX₈X₁₄;

[0021] X₁₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

[0022] R₁ is hydrogen, hydroxy, protected hydroxy or together with R₁₄forms a carbonate;

[0023] R₂ is —OCOR₃₁;

[0024] R_(2a) is hydrogen;

[0025] R₄ is hydrogen, together with R_(4a) forms an oxo, oxirane ormethylene, or together with R_(5a) and the carbon atoms to which theyare attached form an oxetane ring;

[0026] R_(4a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,cyano, hydroxy, —OCOR₃₀, or together with R₄ forms an oxo, oxirane ormethylene;

[0027] R₅ is hydrogen or together with R_(5a) forms an oxo,

[0028] R_(5a) is hydrogen, hydroxy, protected hydroxy, acyloxy, togetherwith R₅ forms an oxo, or together with R₄ and the carbon atoms to whichthey are attached form an oxetane ring;

[0029] R₆ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl,hydroxy, protected hydroxy or together with R_(6a) forms an oxo;

[0030] R_(6a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl,hydroxy, protected hydroxy or together with R₆ forms an oxo;

[0031] R₇ is hydrogen or together with R_(7a) forms an oxo,

[0032] R_(7a) is hydrogen, halogen, protected hydroxy, —OR₂₈, ortogether with R₇ forms an oxo;

[0033] R₉ is hydrogen or together with R_(9a) forms an oxo;

[0034] R_(9a) is hydrogen, hydroxy, protected hydroxy, acyloxy, ortogether with R₉ forms an oxo;

[0035] R₁₀ is hydrogen or together with R_(10a) forms an oxo,

[0036] R_(10a) is hydrogen, —OCOR₂₉, hydroxy, or protected hydroxy, ortogether with R₁₀ forms an oxo;

[0037] R₁₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl,hydroxy, protected hydroxy or together with R₁ forms a carbonate;

[0038] R_(14a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, orheteroaryl;

[0039] R₂₈ is hydrogen, acyl, hydroxy protecting group or a functionalgroup which increases the solubility of the taxane derivative; and

[0040] R₂₉ and R₃₀ are independently hydrogen, alkyl, alkenyl, alkynyl,monocyclic aryl or monocyclic heteroaryl, and

[0041] R₃₁ is substituted phenyl.

[0042] Other objects and features of this invention will be in partapparent and in part pointed out hereinafter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] As used herein “Ar” means aryl; “Ph” means phenyl; “Ac” meansacetyl; “Et” means ethyl; “R” means alkyl unless otherwise defined; “Bu”means butyl; “Pr” means propyl; “TES” means triethylsilyl; “TMS” meanstrimethylsilyl; “TPAP” means tetrapropylammonium perruthenate; “DMAP”means p-dimethylamino pyridine; “DMF” means dimethylformamide; “LDA”means lithium diisopropylamide; “LHMDS” means lithiumhexamethyldisilazide; “LAH” means lithium aluminum hydride; “Red-Al”means sodium bis(2-methoxyethoxy)aluminum hydride; “AIBN” meansazo-(bis)-isobutyronitrile; “10-DAB” means 10-desacetylbaccatin III; FARmeans 2-chloro-1,1,2-trifluorotriethylamine; protected hydroxy means —ORwherein R is a hydroxy protecting group; sulfhydryl protecting group”includes, but is not limited to, hemithioacetals such as 1-ethoxyethyland methoxymethyl, thioesters, or thiocarbonates; “amine protectinggroup” includes, but is not limited to, carbamates, for example,2,2,2-trichloroethylcarbamate or tertbutylcarbamate; and “hydroxyprotecting group” includes, but is not limited to, ethers such asmethyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl,methoxymethyl, 2-methoxypropyl, methoxyethoxymethyl, ethoxyethyl,tetrahydropyranyl, tetrahydrothiopyranyl, and trialkylsilyl ethers suchas trimethylsilyl ether, triethylsilyl ether, dimethylarylsilyl ether,triisopropylsilyl ether and t-butyldimethylsilyl ether; esters such asbenzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetylsuch as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl;and carbonates including but not limited to alkyl carbonates having fromone to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl carbonates having fromone to six carbon atoms and substituted with one or more halogen atomssuch as 2,2,2-trichloroethoxymethyl and 2,2,2-trichloro-ethyl; alkenylcarbonates having from two to six carbon atoms such as vinyl and allyl;cycloalkyl carbonates having from three to six carbon atoms such ascyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl orbenzyl carbonates optionally substituted on the ring with one or moreC₁₋₆ alkoxy, or nitro. Other hydroxyl, sulfhydryl and amine protectinggroups may be found in “Protective Groups in Organic Synthesis” by T. W.Greene, John Wiley and Sons, 1981.

[0044] The alkyl groups described herein, either alone or with thevarious substituents defined herein are preferably lower alkylcontaining from one to six carbon atoms in the principal chain and up to15 carbon atoms. They may be substituted, straight, branched chain orcyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl,cyclopropyl, cyclopentyl, cyclohexyl and the like.

[0045] The alkenyl groups described herein, either alone or with thevarious substituents defined herein are preferably lower alkenylcontaining from two to six carbon atoms in the principal chain and up to15 carbon atoms. They may be substituted, straight or branched chain andinclude ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl,and the like.

[0046] The alkynyl groups described herein, either alone or with thevarious substituents defined herein are preferably lower alkynylcontaining from two to six carbon atoms in the principal chain and up to15 carbon atoms. They may be substituted, straight or branched chain andinclude ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.

[0047] The aryl moieties described herein, either alone or with varioussubstituents, contain from 6 to 15 carbon atoms and include phenyl.Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl,alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl is the morepreferred aryl.

[0048] The heteroaryl moieties described herein, either alone or withvarious substituents, contain from 5 to 15 atoms and include, furyl,thienyl, pyridyl and the like. Substituents include alkanoxy, protectedhydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, andamido.

[0049] The acyloxy groups described herein contain alkyl, alkenyl,alkynyl, aryl or heteroaryl groups.

[0050] The substituents of the substituted alkyl, alkenyl, alkynyl,aryl, and heteroaryl groups and moieties described herein, may be alkyl,alkenyl, alkynyl, aryl, heteroaryl and/or may contain nitrogen, oxygen,sulfur, halogens and include, for example, lower alkoxy such as methoxy,ethoxy, butoxy, halogen such as chloro or fluoro, nitro, amino, andketo.

[0051] In accordance with the present invention, it has been discoveredthat compounds corresponding to structural formula 3 show remarkableproperties, in vitro, and are valuable antileukemia and antitumoragents. Their biological activity has been determined in vitro, usingtubulin assays according to the method of Parness et al., J. CellBiology, 91: 479-487 (1981) and human cancer cell lines, and iscomparable to that exhibited by taxol and taxotere.

[0052] In a preferred embodiment of the present invention, the taxanehas a structure corresponding to taxol or taxotere except for the C2substituent, R₂, which is —OCOR₃₁ wherein R₃₁ is selected from the groupcomprising

[0053] and Z is alkyl, hydroxy, alkoxy, halogen, or trifluoromethyl.That is, R₁₄ and R_(14a) are hydrogen, R₁₀ is hydrogen, R_(10a) ishydroxy or acetoxy, R₉ and R_(9a) together form an oxo, R₇ is hydrogen,R_(7a) is hydroxy, R₅ is hydrogen, R_(5a) and R₄ and the carbons towhich they are attached form an oxetane ring, R_(4a) is acetoxy, R₁ ishydroxy, X₁ is —OH, X₂ is hydrogen, X₃ is phenyl, X₄ is hydrogen, X₅ is—COX₁₀, and X₁₀ is phenyl or t-butoxy and the taxane has the 2′R, 3′Sconfiguration.

[0054] In other embodiments of the present invention, the taxane has astructure which differs from that of taxol or taxotere with respect tothe C2 substituent and at least one other substituent. For example,R_(9a) may be hydrogen, R₉ may be hydrogen, hydroxy, acetoxy or otheracyloxy, R₇ may be acetoxy or other acyloxy or halogen, R_(10a) and R₁₀may each be hydrogen or together form an oxo; X₃ may be selected fromisobutenyl, isopropyl, cyclopropyl, n-butyl, t-butyl, cyclobutyl,cyclohexyl, furyl, thienyl, pyridyl or the substituted derivativesthereof, X₅ may be —COX₁₀ or —COOX₁₀ and X₁₀ may be selected from furyl,thienyl, pyridyl, alkyl substituted furyl or thienyl, tert-, iso- orn-butyl, ethyl, iso- or n-propyl, cyclopropyl, cyclohexyl, allyl,crotyl, 1,3-diethoxy-2-propyl, 2-methoxyethyl, amyl, neopentyl, PhCH₂O—,—NPh₂, —NHnPr, —NHPh, and —NHEt.

[0055] Taxanes having the general formula 3 may be obtained by reactinga β-lactam with alkoxides having the taxane tricyclic or tetracyclicnucleus and a C-13 metallic oxide substituent to form compounds having aβ-amido ester substituent at C-13. The β-lactams have the followingstructural formula:

[0056] wherein X₁-X₅ are as defined above.

[0057] The β-lactams can be prepared from readily available materials,as is illustrated in schemes A and B below:

[0058] reagents: (a) triethylamine, CH₂Cl₂, 25° C., 18 h; (b) 4 equivceric ammonium nitrate, CH₃CN, −10° C., 10 min; (c) KOH, THF, H₂O, 0°C., 30 min. or pyrolidine, pyridine, 25° C., 3 h, (d) TESCl, pyridine,25° C., 30 min or 2-methoxypropene toluene sulfonic acid (cat.), THF, 0°C., 2 h; (e) n-butyllithium, THF, −78° C., 30 min; and an acyl chlorideor chloroformate (X₅═—COX₁₀), sulfonyl chloride (X₅═—COSX₁₀) orisocyanate (X₅═—CONX₈X₁₀); (f) lithium diisopropyl amide, THF −78° C. to−50° C.; (g) lithium hexamethyldisilazide, THF −78° C. to 0° C.; (h)THF, −78° C. to 25° C., 12 h.

[0059] The starting materials are readily available. In scheme A,α-acetoxy acetyl chloride is prepared from glycolic acid, and, in thepresence of a tertiary amine, it cyclocondenses with imines preparedfrom aldehydes and p-methoxyaniline to give1-p-methoxyphenyl-3-acyloxy-4-arylazetidin-2-ones. The p-methoxyphenylgroup can be readily removed through oxidation with ceric ammoniumnitrate, and the acyloxy group can be hydrolyzed under standardconditions familiar to those experienced in the art to provide3-hydroxy-4-arylazetidin-2-ones. In Scheme B,ethyl-α-triethylsilyloxyacetate is readily prepared from glycolic acid.

[0060] In Schemes A and B, X₁ is preferably —OX₆ and X₆ is a hydroxyprotecting group. Protecting groups such as 2-methoxypropyl (“MOP”),1-ethoxyethyl (“EE”) are preferred, but a variety of other standardprotecting groups such as the triethylsilyl group or other trialkyl (oraryl) silyl groups may be used. As noted above, additional hydroxyprotecting groups and the synthesis thereof may be found in “Protectivegroups in Organic Synthesis” by T. W. Greene, John Wiley & Sons, 1981.

[0061] The racemic β-lactams may be resolved into the pure enantiomersprior to protection by recrystallization of the corresponding2-methoxy-2-(trifluoromethyl)phenylacetic esters. However, the reactiondescribed hereinbelow in which the β-amido ester side chain is attachedhas the advantage of being highly diastereoselective, thus permittingthe use of a racemic mixture of side chain precursor.

[0062] The alkoxides having the tricyclic or tetracyclic taxane nucleusand a C-13 metallic oxide or ammonium oxide substituent have thefollowing structural formula:

[0063] wherein R₁-R_(14a) are as previously defined and M comprisesammonium or is a metal optionally selected from the group comprisingGroup IA, Group IIA and transition metals, and preferably, Li, Mg, Na, Kor Ti. Most preferably, the alkoxide has the tetracyclic taxane nucleusand corresponds to the structural formula:

[0064] wherein M, R₂, R_(4a), R₇, R_(7a), R₉, R_(9a), R₁₀, and R_(10a)are as previously defined.

[0065] The alkoxides can be prepared by reacting an alcohol having thetaxane nucleus and a C-13 hydroxyl group with an organometallic compoundin a suitable solvent. Most preferably, the alcohol is a protectedbaccatin III, in particular, 7-O-triethylsilyl baccatin III (which canbe obtained as described by Greene, et al. in JACS 110: 5917 (1988) orby other routes) or 7,10-bis-O-triethylsilyl baccatin III.

[0066] As reported in Greene et al., 10-deacetyl baccatin III isconverted to 7-O-triethylsilyl-10-deacetyl baccatin III according to thefollowing reaction scheme:

[0067] Under what is reported to be carefully optimized conditions,10-deacetyl baccatin III is reacted with 20 equivalents of (C₂H₅)₃SiClat 23° C. under an argon atmosphere for 20 hours in the presence of 50ml of pyridine/mmol of 10-deacetyl baccatin III to provide7-triethylsilyl-10-deacetyl baccatin III (4a) as a reaction product in84-86% yield after purification. The reaction product may thenoptionally be acetylated with 5 equivalents of CH₃COCl and 25 mL ofpyridine/mmol of 4a at 0° C. under an argon atmosphere for 48 hours toprovide 86% yield of 7-O-triethylsilyl baccatin III (4b). Greene, et al.in JACS 110, 5917 at 5918 (1988).

[0068] The 7-protected baccatin III (4b) is reacted with anorganometallic compound such as LHMDS in a solvent such astetrahydrofuran (THF), to form the metal alkoxide13-O-lithium-7-O-triethylsilyl baccatin III as shown in the followingreaction scheme:

[0069] As shown in the following reaction scheme,13-O-lithium-7-O-triethylsilyl baccatin III reacts with a β-lactam inwhich X₁ is preferably —OX₆, (X₆ being a hydroxy protecting group) andX₂-X₅ are as previously defined to provide an intermediate in which theC-7 and C-2′ hydroxyl groups are protected. The protecting groups arethen hydrolyzed under mild conditions so as not to disturb the esterlinkage or the taxane substituents.

[0070] Both the conversion of the alcohol to the alkoxide and theultimate synthesis of the taxane derivative can take place in the samereaction vessel. Preferably, the β-lactam is added to the reactionvessel after formation therein of the alkoxide.

[0071] Compounds of formula 3 of the instant invention are useful forinhibiting tumor growth in animals including humans and are preferablyadministered in the form of a pharmaceutical composition comprising aneffective antitumor amount of compound of the instant invention incombination with a pharmaceutically acceptable carrier or diluent.

[0072] Antitumor compositions herein may be made up in any suitable formappropriate for desired use; e.g., oral, parenteral or topicaladministration. Examples of parenteral administration are intramuscular,intravenous, intraperitoneal, rectal and subcutaneous administration.

[0073] The diluent or carrier ingredients should not be such as todiminish the therapeutic effects of the antitumor compounds.

[0074] Suitable dosage forms for oral use include tablets, dispersiblepowders, granules, capsules, suspensions, syrups, and elixirs. Inertdiluents and carriers for tablets include, for example, calciumcarbonate, sodium carbonate, lactose and talc. Tablets may also containgranulating and disintegrating agents such as starch and alginic acid,binding agents such as starch, gelatin and acacia, and lubricatingagents such as magnesium stearate, stearic acid and talc. Tablets may beuncoated or may be coated by unknown techniques; e.g., to delaydisintegration and absorption. Inert diluents and carriers which may beused in capsules include, for example, calcium carbonate, calciumphosphate and kaolin. Suspensions, syrups and elixirs may containconventional excipients, for example, methyl cellulose, tragacanth,sodium alginate; wetting agents, such as lecithin and polyoxyethylenestearate; and preservatives, e.g., ethyl-p-hydroxybenzoate.

[0075] Dosage forms suitable for parenteral administration includesolutions, suspensions, dispersions, emulsions and the like. They mayalso be manufactured in the form of sterile solid compositions which canbe dissolved or suspended in sterile injectable medium immediatelybefore use. They may contain suspending or dispersing agents known inthe art.

[0076] The water solubility of compounds of formula (3) may be improvedby modification of the C2′ and/or C7 substituents. For instance, watersolubility may be increased if X₁ is —OX₆ and R_(7a) is —OR₂₈, and X₆and R₂₈ are independently hydrogen or —COGCOR¹ wherein

[0077] G is ethylene, propylene, —CH═CH—, 1,2-cyclohexane, or1,2-phenylene,

[0078] R¹=OH base, NR²R³, OR³, SR³, OCH₂CONR⁴R⁵, OH

[0079] R²=hydrogen, methyl

[0080] R³=(CH₂)_(n)NR⁶R⁷; (CH₂)_(n)N^(⊕)R⁶R⁷R⁸X^(⊖)

[0081] n=1 to 3

[0082] R⁴=hydrogen, lower alkyl containing 1 to 4 carbons

[0083] R⁵=hydrogen, lower alkyl containing 1 to 4 carbons, benzyl,hydroxyethyl, CH₂CO₂H, dimethylaminoethyl

[0084] R⁶R⁷=lower alkyl containing 1 or 2 carbons, benzyl or R⁶ and

[0085] R⁷ together with the nitrogen atom of NR⁶R⁷ form the followingrings

[0086] R¹=lower alkyl containing 1 or 2 carbons, benzyl

[0087] X^(⊖)=halide

[0088] base=NH₃, (HOC₂H₄)₃N, N(CH₃)₃, CH₃N(C₂H₄OH)₂, NH₂(CH₂)₆NH₂,N-methylglucamine, NaOH, KOH. The preparation of compounds in which X₁or X₂ is —COGCOR¹ is set forth in Haugwitz U.S. Pat. No. 4,942,184 whichis incorporated herein by reference.

[0089] Alternatively, solubility may be increased when X₁ is —OX₆ and X₆is a radical having the formual —COCX═CHX or —COX—CHX—CHX—SO₂O—M whereinX is hydrogen, alkyl or aryl and M is hydrogen, alkaline metal or anammonio group as described in Kingston et al., U.S. Pat. No. 5,059,699(incorporated herein by reference).

[0090] Taxanes having alternative C9 keto substituent may be prepared byselectively reduced to yield the corresponding C9 β-hydroxy derivative.The reducing agent is preferably a borohydride and, most preferably,tetrabutylammoniumboro-hydride (Bu₄NBH₄) or triacetoxyborohydride.

[0091] As illustrated in Reaction Scheme 1, the reaction of baccatin IIIwith Bu₄NBH₄ in methylene chloride yields 9-desoxo-9β-hydroxybaccatinIII 5. After the C7 hydroxy group is protected with the triethylsilylprotecting group, for example, a suitable side chain may be attached to7-protected-9β-hydroxy derivative 6 as elsewhere described herein.Removal of the remaining protecting groups thus yields 9β-hydroxy-desoxotaxol or other 9β-hydroxytetracylic taxane having a C13 side chain.

[0092] Alternatively, the C13 hydroxy group of 7-protected-9β-hydroxyderivative 6 may be protected with trimethylsilyl or other protectinggroup which can be selectively removed relative to the C7 hydroxyprotecting group as illustrated in Reaction Scheme 2, to enable furtherselective manipulation of the various substituents of the taxane. Forexample, reaction of 7,13-protected-9β-hydroxy derivative 7 with KHcauses the acetate group to migrate from C10 to C9 and the hydroxy groupto migrate from C9 to C10, thereby yielding 10-desacetyl derivative 8.Protection of the C10 hydroxy group of 10-desacetyl derivative 8 withtriethylsilyl yields derivative 9. Selective removal of the C13 hydroxyprotecting group from derivative 9 yields derivative 10 to which asuitable side chain may be attached as described above.

[0093] As shown in Reaction Scheme 3, 10-oxo derivative 11 can beprovided by oxidation of 10-desacetyl derivative 8. Thereafter, the C13hydroxy protecting group can be selectively removed followed byattachment of a side chain as described above to yield9-acetoxy-10-oxo-taxol or other 9-acetoxy-10-oxotetracylic taxaneshaving a C13 side chain. Alternatively, the C9 acetate group can beselectively removed by reduction of lo-oxo derivative 11 with a reducingagent such as samarium diiodide to yield 9-desoxo-10-oxo derivative 12from which the C13 hydroxy protecting group can be selectively removedfollowed by attachment of a side chain as described above to yield9-desoxo-10-oxo-taxol or other 9-desoxo-10-oxotetracylic taxanes havinga C13 side chain.

[0094] Reaction Scheme 4 illustrates a reaction in which 10-DAB isreduced to yield pentaol 13. The C7 and C10 hydroxyl groups of pentaol13 can then be selectively protected with the triethylsilyl or anotherprotecting group to produce triol 14 to which a C13 side chain can beattached as described above or, alternatively, after furthermodification of the tetracylic substituents.

[0095] Taxanes having C9 and/or C10 acyloxy substituents other thanacetate can be prepared using 10-DAB as a starting material asillustrated in Reaction Scheme 5. Reaction of 10-DAB with triethylsilylchloride in pyridine yields 7-protected 10-DAB 15. The C10 hydroxysubstituent of 7-protected 10-DAB 15 may then be readily acylated withany standard acylating agent to yield derivative 16 having a new C10acyloxy substituent. Selective reduction of the C9 keto substituent ofderivative 16 yields 9β-hydroxy derivative 17 to which a C13 side chainmay be attached. Alternatively, the C10 and C9 groups can be caused tomigrate as set forth in Reaction Scheme 2, above.

[0096] Taxanes having alternative C2 and/or C4 esters can be preparedusing baccatin III and 10-DAB as starting materials. The C2 and/or C4esters of baccatin III and 10-DAB can be selectively reduced to thecorresponding alcohol(s) using reducing agents such as LAH or Red-Al,and new esters can thereafter be substituted using standard acylatingagents such as anhydrides and acid chlorides in combination with anamine such as pyridine, triethylamine, DMAP, or diisopropyl ethyl amine.Alternatively, the C2 and/or C4 alcohols may be converted to new C2and/or C4 esters through formation of the corresponding alkoxide bytreatment of the alcohol with a suitable base such as LDA followed by anacylating agent such as an acid chloride.

[0097] Baccatin III and 10-DAB analogs having different substituents atC2 and/or C4 can be prepared as set forth in Reaction Schemes 6-10. Tosimplify the description, 10-DAB is used as the starting material. Itshould be understood, however, that baccatin III derivatives or analogsmay be produced using the same series of reactions (except for theprotection of the C10 hydroxy group) by simply replacing 10-DAB withbaccatin III as the starting material. Derivatives of the baccatin IIIand 10-DAB analogs having different substituents at C2 and at least oneother position, for instance C1, C4, C7, C9, C10 and C13, can then beprepared by carrying out any of the other reactions described herein andany others which are within the level of skill in the art.

[0098] In Reaction Scheme 6, protected 10-DAB 3 is converted to thetriol 18 with lithium aluminum hydride. Triol 18 is then converted tothe corresponding C4 ester using Cl₂CO in pyridine followed by anucleophilic agent (e.g., Grignard reagents or alkyllithium reagents).

[0099] Deprotonation of triol 18 with LDA followed by introduction of anacid chloride selectively gives the C4 ester. For example, when acetylchloride was used, triol 18 was converted to 1,2 diol 4 as set forth inReaction Scheme 7.

[0100] Triol 18 can also readily be converted to the 1,2 carbonate 19.Acetylation of carbonate 19 under vigorous standard conditions providescarbonate 21 as described in Reaction Scheme 8; addition ofalkyllithiums or Grignard reagents to carbonate 19 provides the C2 esterhaving a free hydroxyl group at C4 as set forth in Reaction Scheme 6.

[0101] As set forth in Reaction Scheme 9, other C4 substituents can beprovided by reacting carbonate 19 with an acid chloride and a tertiaryamine to yield carbonate 22 which is then reacted with alkyllithiums orGrignard reagents to provide 10-DAB derivatives having new substituentsat C2.

[0102] Alternatively, baccatin III may be used as a starting materialand reacted as shown in Reaction Scheme 10. After being protected at C7and C13, baccatin III is reduced with LAH to produce 1,2,4,10 tetraol24. Tetraol 24 is converted to carbonate 25 using Cl₂CO and pyridine,and carbonate 25 is acylated at C10 with an acid chloride and pyridineto produce carbonate 26 (as shown) or with acetic anhydride and pyridine(not shown). Acetylation of carbonate 26 under vigorous standardconditions provides carbonate 27 which is then reacted with alkyllithiums to provide the baccatin III derivatives having new substituentsat C2 and C10.

[0103] 10-desacetoxy derivatives of baccatin III and 10-desoxyderivatives of 10-DAB may be prepared by reacting baccatin III or 10-DAB(or their derivatives) with samarium diiodide. Reaction between thetetracyclic taxane having a C10 leaving group and samarium diiodide maybe carried out at 0° C. in a solvent such as tetrahydrofuran.Advantageously, the samarium diiodide selectively abstracts the C10leaving group; C13 side chains and other substituents on the tetracyclicnucleus remain undisturbed. Thereafter, the C9 keto substituent may bereduced to provide the corresponding 9-desoxo-9β-hydroxy-10-desacetyoxyor 10-desoxy derivatives as otherwise described herein.

[0104] C7 dihydro and other C7 substituted taxanes can be prepared asset forth in Reaction Schemes 11, 12 and 12a.

[0105] As shown in Reaction Scheme 12, Baccatin III may be convertedinto 7-fluoro baccatin III by treatment with FAR at room temperature inTHF solution. Other baccatin derivatives with a free C7 hydroxyl groupbehave similarly. Alternatively, 7-chloro baccatin III can be preparedby treatment of baccatin III with methane sulfonyl chloride andtriethylamine in methylene chloride solution containing an excess oftriethylamine hydrochloride.

[0106] Taxanes having C7 acyloxy substituents can be prepared as setforth in Reaction Scheme 12a, 7,13-protected 10-oxo-derivative 11 isconverted to its corresponding C13 alkoxide by selectively removing theC13 protecting group and replacing it with a metal such as lithium. Thealkoxide is then reacted with a β-lactam or other side chain precursor.Subsequent hydrolysis of the C7 protecting groups causes a migration ofthe C7 hydroxy substituent to C10, migration of the C10 oxo substituentto C9, and migration of the C9 acyloxy substituent to C7.

[0107] A wide variety of tricyclic taxanes are naturally occurring, andthrough manipulations analogous to those described herein, anappropriate side chain can be attached to the C13 oxygen of thesesubstances. Alternatively, as shown in Reaction Scheme 13,7-O-triethylsilyl baccatin III can be converted to a tricyclic taxanethrough the action of trimethyloxonium tetrafluoroborate in methylenechloride solution. The product diol then reacts with lead tetraacetateto provide the corresponding C4 ketone.

[0108] Recently a hydroxylated taxane (14-hydroxy-10-deacetylbaccatinIII) has been discovered in an extract of yew needles (C&EN, p 36-37,Apr. 12, 1993). Derivatives of this hydroxylated taxane having thevarious C2, C4, etc. functional groups described above may also beprepared by using this hydroxylated taxane. In addition, the C14 hydroxygroup together with the C1 hydroxy group of 10-DAB can be converted to a1,2-carbonate as described in C&EN or it may be converted to a varietyof esters or other functional groups as otherwise described herein inconnection with the C2, C4, C7, C9, C10 and C13 substituents.

[0109] The following examples are provided to more fully illustrate theinvention.

[0110] (64-4)

Preparation of2-desbenzoyl-2-(3-methoxybenzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxycarbonyl)taxol

[0111] To a solution of2-desbenzoyl-2-(3-methoxybenzoyl)-10-deacetyl-7,10-bis(triethylsilyl)baccatinIII (48.2 mg, 0.060 mmol) in 0.5 mL of THF at −45° C. was added dropwise0.066 mL of a 1.00 M solution of LiN(SiMe₃)₂ in hexane. After 0.5 h at−45° C., a solution ofcis-1-(t-butoxycarbonyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (90mg, 0.240 mmol) in 0.5 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before0.5 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 70.8 mg of amixture containing(2′R,3′S)-2′,7,10-tris(triethylsilyl)-2-desbenzoyl-2-(3-methoxy-benzoyl)-10-deacetyl-N-debenzoyl-N-(t-butoxycarbonyl)taxoland a very small amount of the (2′S,3′R) isomer.

[0112] To a solution of 70.8 mg of the mixture obtained from theprevious reaction in 4 mL of acetonitrile and 0.19 mL of pyridine at 0°C. was added 0.52 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 50.3 mg of material which was purified byrecrystallization to give 43.1 mg (86%) of2-desbenzoyl-2-(3-methoxybenzoyl)-10-deacetyl-N-debenzoyl-N-(t-butoxy-carbonyl)taxol.

[0113] m.p.162-164° C.; [α]²⁵ _(Na) −61.6° (c 0.790, CHCl₃).

[0114]¹H NMR (CDCl₃, 300 MHz) δ7.67 (m, 2H, methoxybenzoate, ortho),7,36 (m, 6H, aromatic), 7.15 (m, 1H, methoxybenzoate), 6.19 (m, 1H,H13), 5.65 (d, J=6.9 Hz, 1H, H2β), 5.50 (m, 1H, NH), 5.21 (m, 2H, H3′,H10), 4.95 (dd, J=7.8, 1.8 Hz, 1H, H5), 4.60 (m, 1H, H2′), 4.33 (d,J=8.7 Hz, 1H, H20α), 4.23 (m, 1H, H7), 4.17 (d, J=8.7 Hz, 1H, H20β),3.89 (d, J=6.9 Hz, 1H, H3), 3.86 (s, 3H, methoxy), 3.56 (m, 1H, 2′OH),2.55 (m, 1H, H6α), 2.34 (s, 3H, 4Ac), 2.23 (m, 2H, H14), 1.83 (s, 3H,Me18), 1.79 (m, 1H, H6β), 1.73 (s, 3H, Me19), 1.32 (s, 9H, t-butyl),1.22 (s, 3H, Me17), 1.11 (s, 3H, Me16).

[0115] (65-1)

Preparation of2-desbenzoyl-2-(3-methylbenzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxycarbonyl)taxol

[0116] To a solution of2-desbenzoyl-2-(3-methylbenzoyl)-10-deacetyl-7,10-bis(triethylsilyl)baccatinIII (47.2 mg, 0.060 mmol) in 0.5 mL of THF at −45° C. was added dropwise0.066 mL of a 1.00 M solution of LiN(SiMe₃)₂ in hexane. After 0.5 h at−45° C., a solution ofcis-1-(t-butoxycarbonyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (90mg, 0.240 mmol) in 0.5 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before0.5 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 70.0 mg of amixture containing(2′R,3′S)-2′,7,10-tris(triethylsilyl)-2-desbenzoyl-2-(3-methyl-benzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxycarbonyl)taxoland a very small amount of the (2′S,3′R) isomer.

[0117] To a solution of 70.0 mg of the mixture obtained from theprevious reaction in 4 mL of acetonitrile and 0.19 mL of pyridine at 0°C. was added 0.52 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 49.3 mg of material which was purified byrecrystallization to give 41.9 mg (85%) of2-desbenzoyl-2-(3-methylbenzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxy-carbonyl)taxol.

[0118] m.p.169-171° C.; [α]²⁵ _(Na) −60.4° (c 0.510, CHCl₃).

[0119]¹H NMR (CDCl₃, 300 MHz) δ7.91 (m, 2H, benzoate), 7,38 (m, 7H,aromatic), 6.21 (m, 1H, H13), 5.65 (d, J=7.2 Hz, 1H, H2β), 5.42 (m, 1H,NH), 5.26 (m, 1H, H3′), 5.20 (d, J=1.2 Hz, 1H, H10), 4.94 (m, 1H, H5),4.61 (m, 1H, H2′), 4.31 (d, J=8.7 Hz, 1H, H20α), 4.24 (m, 1H, H7), 4.17(d, J=8.7 Hz, 1H, H20β), 3.91 (d, J=7.2 Hz, 1H, H3), 3.37 (m, 1H, 2′OH),2.57 (m, 1H, H6α), 2.43 (s, 3H, 4Ac), 2.26 (m, 2H, H14), 2.17 (s, 3H,methylbenzoate), 1.84 (s, 3H, Me18), 1.79 (m, 1H, H6β), 1.74 (s, 3H,Me19), 1.33 (s, 9H, t-butyl), 1.22 (s, 3H, Me17), 1.12 (s, 3H, Me16).

EXAMPLE 3

[0120] (65-2)

Preparation of2-desbenzoyl-2-(3-chlorobenzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxycarbonyl)taxol

[0121] To a solution of2-desbenzoyl-2-(3-chlorobenzoyl)-10-deacetyl-7,10-bis(triethylsilyl)baccatinIII (48.4 mg, 0.060 mmol) in 0.5 mL of THF at −45° C. was added dropwise0.066 mL of a 1.00 M solution of LiN(SiMe₃)₂ in hexane. After 0.5 h at−45° C., a solution ofcis-1-(t-butoxycarbonyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (90mg, 0.240 mmol) in 0.5 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before0.5 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 71 mg of a mixturecontaining(2′R,3′S)-2′,7,10-tris(tri-ethylsilyl)-2-desbenzoyl-2-(3-chloro-benzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxycarbonyl)taxoland a very small amount of the (2′S,3′R) isomer.

[0122] To a solution of 71 mg of the mixture obtained from the previousreaction in 4 mL of acetonitrile and 0.19 mL of pyridine at 0° C. wasadded 0.52 mL of 48% aqueous HF. The mixture was stirred at 0° C. for 3h, then at 25° C. for 13 h, and partitioned between saturated aqueoussodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetatesolution gave 50.5 mg of material which was purified byrecrystallization to give 40.4 mg (80%) of2-desbenzoyl-2-(3-chlorobenzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxy-carbonyl)taxol.

[0123] m.p.149-150° C.; [α]²⁵ _(Na) −53.3° (c 0.510, CHCl₃).

[0124]¹H NMR (CDCl₃, 300 MHz) δ8.11 (br s, 1H, chlorobenzoate ortho),7.98 (d, J=7.5 Hz, 1H, chlorobenzoate ortho), 7.59 (m, 1H,chlorobenzoate), 7.45 (t, J=7.5 Hz, 1H, chlorobenzoate), 7.38 (m, 5H,aromatic), 6.18 (m, 1H, H13), 5.62 (d, J=7.2 Hz, 1H, H2β), 5.41 (m, 1H,H3′), 5.24 (m, 1H, NH), 5.20 (d, J=1.0 Hz, 1H, H10), 4.95 (dd, J=9.3,1.2 Hz, 1H, H5), 4.59 (m, 1H, H2′), 4.30 (d, J=8.4 Hz, 1H, H20α), 4.23(m, 1H, H7), 4.15 (d, J=8.4 Hz, 1H, H20β), 3.91 (d, J=7.2 Hz, 1H, H3),3.35 (m, 1H, 2′OH), 2.58 (m, 1H, H6α), 2.36 (s, 3H, 4Ac), 2.24 (m, 2H,H14), 1.84 (s, 3H, Me18), 1.79 (m, 1H, H6β), 1.75 (s, 3H, Me19), 1.34(s, 9H, t-butyl), 1.23 (s, 3H, Me17), 1.12 (s, 3H, Me16).

EXAMPLE 4

[0125] (65-3)

Preparation of2-desbenzoyl-2-(3-trifluoromethylbenzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxycarbonyl)taxol

[0126] To a solution of2-desbenzoyl-2-(3-trifluoromethyl-benzoyl)-10-deacetyl-7,10-bis(triethylsilyl)baccatinIII (50.4 mg, 0.060 mmol) in 0.5 mL of THF at −45° C. was added dropwise0.066 mL of a 1.00 M solution of LiN(SiMe₃)₂ in hexane. After 0.5 h at−45° C., a solution ofcis-1-(t-butoxy-carbonyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (90mg, 0.240 mmol) in 0.5 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before0.5 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 73.0 mg of amixture containing(2′R,3′S)-2′,7,10-tris(triethylsilyl)-2-desbenzoyl-2-(3-trifluoromethylbenzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxycarbonyl)taxoland a very small amount of the (2′S,3′R) isomer.

[0127] To a solution of 73.0 mg of the mixture obtained from theprevious reaction in 4 mL of acetonitrile and 0.19 mL of pyridine at 0°C. was added 0.52 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 52.6 mg of material which was purified byrecrystallization to give 41.0 mg (78%) of2-desbenzoyl-2-(3-trifluoromethylbenzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxycarbonyl)taxol.

[0128] m.p.140-142° C.; [α]²⁵ _(Na) −50.4° (c 1.055, CHCl₃).

[0129]¹H NMR (CDCl₃, 300 MHz) δ8.43 (s, 1H, benzoate, ortho), 8.29 (d,J=7.8 Hz, 1H, benzoate ortho), 7.88 (d, J=7.8 Hz, 1H, benzoate), 7.66(t, J=7.8 Hz, 1H, benzoate), 7,38 (m, 5H, aromatic), 6.17 (m, 1H, H13),5.65 (d, J=7.2 Hz, 1H, H2β), 5.38 (m, 1H, NH), 5.23 (m, 1H, H3′), 5.21(d, J=1.8 Hz, 1H, H10), 4.95 (m, 1H, H5), 4.58 (m, 1H, H2′), 4.27 (d,J=8.7 Hz, 1H, H20α), 4.21 (m, 1H, H7), 4.15 (d, J=8.7 Hz, 1H, H20β),3.93 (d, J=7.2 Hz, 1H, H3), 3.35 (m, 1H, 2′OH), 2.59 (m, 1H, H6α), 2.33(s, 3H, 4Ac), 2.23 (m, 2H, H14), 1.85 (s, 3H, Me18), 1.79 (m, 1H, H6β),1.76 (s, 3H, Me19), 1.32 (s, 9H, t-butyl), 1.22 (s, 3H, Me17), 1.11 (s,3H, Me16).

EXAMPLE 5

[0130] (65-4)

Preparation of2-desbenzoyl-2-(4-methoxybenzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxycarbonyl)taxol

[0131] To a solution of2-desbenzoyl-2-(4-methoxybenzoyl)-10-deacetyl-7,10-bis(triethylsilyl)baccatinIII (48.2 mg, 0.060 mmol) in 0.5 mL of THF at −45° C. was added dropwise0.066 mL of a 1.00 M solution of LiN(SiMe₃)₂ in hexane. After 0.5 h at−45° C., a solution ofcis-1-(t-butoxycarbonyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (90mg, 0.240 mmol) in 0.5 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before0.5 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 71 mg of a mixturecontaining(2′R,3′S)-2′,7,10-tris(triethylsilyl)-2-desbenzoyl-2-(4-methoxy-benzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxycarbonyl)taxoland a very small amount of the (2′S,3′R) isomer.

[0132] To a solution of 71 mg of the mixture obtained from the previousreaction in 4 mL of acetonitrile and 0.19 mL of pyridine at 0° C. wasadded 0.52 mL of 48% aqueous HF. The mixture was stirred at 0° C. for 3h, then at 25° C. for 13 h, and partitioned between saturated aqueoussodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetatesolution gave 50.3 mg of material which was purified byrecrystallization to give 45.2 mg (90%) of2-desbenzoyl-2-(4-methoxybenzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxycarbonyl)taxol.

[0133] m.p.160-162° C.; [α]²⁵ _(Na) −47.6° (c 0.290, CHCl₃).

[0134]¹H NMR (CDCl₃, 300 MHz) δ8.05 (dd, J=9.0, 2H, methoxybenzoate,ortho), 7.38 (m, 5H, aromatic), 6.96 (dd, J=9.0, 2H, methoxybenzoate,meta), 6.23 (m, 1H, H13), 5.64 (d, J=7.2 Hz, 1H, H2β), 5.42 (m, 1H,H3′), 5.27 (m, 1H, NH), 5.19 (d, J=1.2 Hz, 1H, H10), 4.93 (dd, J=7.8,1.8 Hz, 1H, H5), 4.62 (m, 1H, H2′), 4.31 (d, J=9.0 Hz, 1H, H20α), 4.24(m, 1H, H7), 4.19 (d, J=9.0 Hz, 1H, H20β), 3.89 (d, J=7.2 Hz, 1H, H3),3.65 (s, 3H, methoxy), 3.32 (m, 1H, 2′OH), 2.58 (m, 1H, H6α), 2.37 (s,3H, 4Ac), 2.26 (m, 2H, H14), 1.85 (s, 3H, Me18), 1.78 (m, 1H, H6β), 1.75(s, 3H, Me19), 1.34 (s, 9H, t-butyl), 1.23 (s, 3H, Me17), 1.12 (s, 3H,Me16).

EXAMPLE 6

[0135] (66-1)

Preparation of2-desbenzoyl-2-(4-chlorobenzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxycarbonyl)taxol

[0136] To a solution of2-desbenzoyl-2-(4-chlorobenzoyl)-10-deacetyl-7,10-bis(triethylsilyl)baccatinIII (48.4 mg, 0.060 mmol) in 0.5 mL of THF at −45° C. was added dropwise0.066 mL of a 1.00 M solution of LiN(SiMe₃)₂ in hexane. After 0.5 h at−45° C., a solution ofcis-1-(t-butoxycarbonyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (90mg, 0.240 mmol) in 0.5 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before0.5 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 71 mg of a mixturecontaining(2′R,3′S)-2′,7,10-tris(triethylsilyl)-2-desbenzoyl-2-(4-chlorobenzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxycarbonyl)taxoland a very small amount of the (2′S,3′R) isomer.

[0137] To a solution of 71 mg of the mixture obtained from the previousreaction in 4 mL of acetonitrile and 0.19 mL of pyridine at 0° C. wasadded 0.52 mL of 48% aqueous HF. The mixture was stirred at 0° C. for 3h, then at 25° C. for 13 h, and partitioned between saturated aqueoussodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetatesolution gave 51 mg of material which was purified by recrystallizationto give 37.9 mg (75%) of2-desbenzoyl-2-(4-chlorobenzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxycarbonyl)taxol.

[0138] m.p.160-161° C.; [α]²⁵ _(Na) −46.0° (c 0.104, CHCl₃).

[0139]¹H NMR (CDCl₃, 300 MHz) δ8.03 (d, J=8.7 Hz, 2H, chlorobenzoateortho), 7.48 (d, J=8.7 Hz, 2H, chlorobenzoate meta), 7.38 (m, 5H,aromatic), 6.23 (m, 1H, H13), 5.64 (d, J=7.2 Hz, 1H, H2β), 5.45 (m, 1H,H3′), 5.26 (m, 1H, NH), 5.20 (d, J=1.2 Hz, 1H, H10), 4.93 (d, J=7.8 Hz,1H, H5), 4.63 (m, 1H, H2′), 4.28 (d, J=8.2 Hz, 1H, H20α), 4.22 (m, 1H,H7), 4.15 (d, J=8.2 Hz, 1H, H20β), 3.90 (d, J=7.2 Hz, 1H, H3), 3.36 (m,1H, 2′OH), 2.58 (m, 1H, H6α), 2.37 (s, 3H, 4Ac), 2.25 (m, 2H, H14), 1.85(s, 3H, Me18), 1.80 (m, 1H, H6β), 1.75 (s, 3H, Me19), 1.32 (s, 9H,t-butyl), 1.23 (s, 3H, Me17), 1.11 (s, 3H, Me16).

EXAMPLE 7

[0140] (66-2)

Preparation of2-desbenzoyl-2-(4-fluorobenzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxycarbonyl)taxol

[0141] To a solution of2-desbenzoyl-2-(4-fluorobenzoyl)-10-deacetyl-7,10-bis(triethylsilyl)baccatinIII (47.5 mg, 0.060 mmol) in 0.5 mL of THF at −45° C. was added dropwise0.066 mL of a 1.00 M solution of LiN(SiMe₃)₂ in hexane. After 0.5 h at−45° C., a solution ofcis-1-(t-butoxycarbonyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (90mg, 0.240 mmol) in 0.5 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before0.5 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 70 mg of a mixturecontaining (2′R,3′S)-2′,7,10-tris(triethylsilyl)-2-desbenzoyl-2-(4-fluoro-benzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxycarbonyl)taxoland a very small amount of the (2′S,3′R) isomer.

[0142] To a solution of 70 mg of the mixture obtained from the previousreaction in 4 mL of acetonitrile and 0.19 mL of pyridine at 0° C. wasadded 0.52 mL of 48% aqueous HF. The mixture was stirred at 0° C. for 3h, then at 25° C. for 13 h, and partitioned between saturated aqueoussodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetatesolution gave 49.5 mg of material which was purified byrecrystallization to give 42.0 mg (85%) of2-desbenzoyl-2-(4-fluorobenzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxycarbonyl)taxol.

[0143] m.p. 158-160° C.; [α]²⁵ _(Na) −47.6° (c 0.290, CHCl₃).

[0144]¹H NMR (CDCl₃, 300 MHz) δ8.13 (m, 2H, fluorobenzoate ortho), 7.38(m, 5H, aromatic), 7.17 (m, 2H, fluorobenzoate), 6.23 (m, 1H, H13), 5.64(d, J=7.2 Hz, 1H, H2β), 5.41 (d, J=9.9 Hz, 1H, H3′), 5.26 (m, 1H, NH),5.20 (d, J=1.2 Hz, 1H, H10), 4.93 (dd, J=9.9, 2.1 Hz, 1H, H5), 4.63 (m,1H, H2′), 4.28 (d, J=8.2 Hz, 1H, H20α), 4.24 (m, 1H, H7), 4.17 (d, J=8.2Hz, 1H, H20β), 3.91 (d, J=7.2 Hz, 1H, H3), 3.32 (m, 1H, 2′OH), 2.58 (m,1H, H6α), 2.37 (s, 3H, 4Ac), 2.25 (m, 2H, H14), 1.85 (s, 3H, Me18), 1.80(m, 1H, H6β), 1.75 (s, 3H, Me19), 1.33 (s, 9H, t-butyl), 1.25 (s, 3H,Me17), 1.12 (s, 3H, Me16).

EXAMPLE 8

[0145] (68-1)

Preparation ofN-desbenzoyl-N-(t-butoxycarbonyl)-2-desbenzoyl-2-(2-trifluoromethylbenzoyl)-10-desacetyltaxol

[0146] To a solution of2-desbenzoyl-2-(2-trifluoromethyl-benzoyl)-10-deacetyl-7,10-(bis)-O-triethylsilylbaccatin III (50.4 mg, 0.060 mmol) in 0.5 mL of THF at −45° C. was addeddropwise 0.066 mL of a 1.00 M solution of LiN(SiMe₃)₂ in hexane. After0.5 h at −45° C., a solution ofcis-1-(t-butoxy-carbonyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (90mg, 0.240 mmol) in 0.5 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before0.5 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 73.0 mg of amixture containing(2′R,3′S)-2′,7,10-(tris)-O-triethyl-silyl-N-desbenzoyl-N-(t-butoxycarbonyl)-2-desbenzoyl-2-(2-trifluoromethylbenzoyl)-10-desacetyltaxol and a very small amount of the (2′S,3′R) isomer.

[0147] To a solution of 73.0 mg of the mixture obtained from theprevious reaction in 4 mL of acetonitrile and 0.19 mL of pyridine at 0°C. was added 0.52 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 52.6 mg of material which was purified byrecrystallization to give 39.4 mg (75%) ofN-desbenzoyl-N-(t-butoxycarbonyl)-2-desbenzoyl-2-(2-trifluoromethyl-benzoyl)-10-desacetyltaxol.

[0148] m.p.121-123° C.; [α]²⁵ _(Na) −34.2° (c 0.760, CHCl₃).

[0149]¹H NMR (CDCl₃, 300 MHz) δ8.10 (m, 1H, benzoate, ortho), 7.82 (d,J=7.5 Hz, 1H, benzoate), 7.70 (m, 2H, benzoate), 7,35 (m, 5H, aromatic),6.24 (m, 1H, H13), 5.64 (d, J=7.2 Hz, 1H, H2β), 5.46 (m, 1H, NH), 5.28(m, 1H, H3′), 5.19 (d, J=1.8 Hz, 1H, H10), 4.89 (dd, J=8.7, 1.2 Hz, 1H,H5), 4.63 (m, 1H, H2′), 4.26 (d, J=8.1 Hz, 1H, H20α), 4.17 (m, 2H, H7,H20β), 3.90 (d, J=7.2 Hz, 1H, H3), 3.35 (m, 1H, 2′OH), 2.56 (m, 1H,H6α), 2.39 (m, 2H, H14), 2.24 (s, 3H, 4Ac), 1.87 (s, 3H, Me18), 1.84 (m,1H, H6β), 1.76 (s, 3H, Me19), 1.38 (s, 9H, t-butyl), 1.24 (s, 3H, Me17),1.11 (s, 3H, Me16).

EXAMPLE 9

[0150] (68-2)

Preparation of N-desbenzoyl-N-(t-butoxycarbonyl)-2-5desbenzoyl-2-(2-methylbenzoyl)-10-desacetyl taxol

[0151] To a solution of2-desbenzoyl-2-(2-methylbenzoyl)-10-desacetyl-7,10-(bis)-O-triethylsilylbaccatin III (47.2 mg, 0.060 mmol) in 0.5 mL of THF at −45° C. was addeddropwise 0.066 mL of a 1.00 M solution of LiN(SiMe₃)₂ in hexane. After0.5 h at −45° C., a solution ofcis-1-(t-butoxycarbonyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (90mg, 0.240 mmol) in 0.5 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before0.5 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 70.0 mg of amixture containing(2′R,3′S)-2′,7,10-(tris)-O-triethylsilyl-N-desbenzoyl-N-(t-butoxy-carbonyl)-2-desbenzoyl-2-(2-methylbenzoyl)-10-desacetyltaxol and a very small amount of the (2′S,3′R) isomer.

[0152] To a solution of 70.0 mg of the mixture obtained from theprevious reaction in 4 mL of acetonitrile and 0.19 mL of pyridine at 0°C. was added 0.52 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 49.3 mg of material which was purified byrecrystallization to give 44.4 mg (90%) of2-desbenzoyl-2-(2-methylbenzoyl)-10-deacetyl-N-desbenzoyl-N-(t-butoxy-carbonyl)taxol.

[0153] m.p.129-131° C.; [α]²⁵ _(Na) −50.8° (c 0.750, CHCl₃).

[0154]¹H NMR (CDCl₃, 300 MHz) δ8.05 (m, 1H, benzoate), 7,38 (m, 8H,aromatic), 6.21 (m, 1H, H13), 5.65 (d, J=6.6 Hz, 1H, H2β), 5.46 (m, 1H,NH), 5.24 (m, 1H, H3′), 5.20 (d, J=0.9 Hz, 1H, H10), 4.91 (dd, J=9.3,1.5 Hz, 1H, H5), 4.60 (br s, 1H, H2′), 4.25 (d, J=8.1 Hz, 1H, H20α),4.24 (m, 1H, H7), 4.17 (d, J=8.1 Hz, 1H, H20β), 3.88 (d, J=6.6 Hz, 1H,H3), 3.37 (m, 1H, 2′OH), 2.63 (s, 3H, methylbenzoate), 2.57 (m, 1H,H6α), 2.30 (s, 3H, 4Ac), 2.58 (m, 2H, H14), 1.83 (s, 3H, Me18), 1.79 (m,1H, H6β), 1.75 (s, 3H, Me19), 1.37 (s, 9H, t-butyl), 1.24 (s, 3H, Me17),1.13 (s, 3H, Me16).

EXAMPLE 10

[0155] (73-4)

Preparation ofN-desbenzoyl-N-(t-butoxycarbonyl)-2-desbenzoyl-2-(3,5-bis(trifluoromethyl)benzoyl)-10-desacetyltaxol

[0156] To a solution of2-desbenzoyl-2-(3,5-bis(tri-fluoromethyl)benzoyl)-7,10-(bis)-O-triethylsilyl-10-desacetylbaccatin III (51.3 mg, 0.060 mmol) in 0.5 mL of THF at −45° C. was addeddropwise 0.066 mL of a 1.00 M solution of LiN(SiMe₃)₂ in hexane. After0.5 h at −45° C., a solution ofcis-1-(t-butoxycarbonyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (90mg, 0.240 mmol) in 0.5 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before0.5 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 73.9 mg of amixture containing(2′R,3′S)-2′,7,10-(tris)-O-triethyl-silyl-N-desbenzoyl-N-(t-butoxycarbonyl)-2-desbenzoyl-2-(3,5-bis(tri-fluoromethyl)benzoyl)-10-desacetyltaxol and a very small amount of the (2′S,3′R) isomer.

[0157] To a solution of 73.9 mg of the mixture obtained from theprevious reaction in 4 mL of acetonitrile and 0.19 mL of pyridine at 0°C. was added 0.52 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 53.4 mg of material which was purified byrecrystallization to give 49.1 mg (92%) ofN-desbenzoyl-N-(t-butoxycarbonyl)-2-desbenzoyl-2-(3,5-bis(trifluoromethyl)-benzoyl)-10-desacetyltaxol.

[0158] m.p.141-143° C.; [α]²⁵ _(Na) −43.6° (c 0.730, CHCl₃).

[0159]¹H NMR (CDCl₃, 300 MHz) δ8.59 (s, 2H, benzoate, ortho), 8.12 (s,1H, benzoate para), 7.37 (m, 5H, aromatic), 6.14 (m, 1H, H13), 5.64 (d,J=7.2 Hz, 1H, H2β), 5.36 (m, 1H, NH), 5.21 (d, J=1.2 Hz, 1H, H10), 5.18(m, 1H, H3′), 4.97 (dd, J=9.6, 2.1 Hz, 1H, H5), 4.58 (m, 1H, H2′), 4.19(m, 3H, H20, H7), 3.95 (d, J=7.2 Hz, 1H, H3), 3.39 (m, 1H, 2′OH), 2.59(m, 1H, H6α), 2.30 (s, 3H, 4Ac), 2.25 (m, 2H, H14), 1.85 (s, 3H, Me18),1.79 (m, 1H, H6β), 1.75 (s, 3H, Me19), 1.32 (s, 9H, t-butyl), 1.22 (s,3H, Me17), 1.13 (s, 3H, Me16).

EXAMPLE 11

[0160] (74-1)

Preparation ofN-desbenzoyl-N-(t-butoxycarbonyl)-2-desbenzoyl-2-(3,5-dimethylbenzoyl)-10-desacetoxytaxol

[0161] To a solution of2-desbenzoyl-2-(3,5-dimethyl-benzoyl)-7,10-(bis)-O-triethylsilyl-10-desacetylbaccatin III (48.1 mg, 0.060 mmol) in 0.5 mL of THF at −45° C. was addeddropwise 0.066 mL of a 1.00 M solution of LiN(SiMe₃)₂ in hexane. After0.5 h at −45° C., a solution ofcis-1-(t-butoxy-carbonyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (90mg, 0.240 mmol) in 0.5 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before0.5 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 70.1 mg of amixture containing(2′R,3′S)-2′,7,10-(tris)-O-triethyl-silyl-N-desbenzoyl-N-(t-butoxycarbonyl)-2-desbenzoyl-2-(3,5-dimethylbenzoyl)-10-desacetoxytaxol and a very small amount of the (2′S,3′R) isomer.

[0162] To a solution of 70.1 mg of the mixture obtained from theprevious reaction in 4 mL of acetonitrile and 0.19 mL of pyridine at 0°C. was added 0.52 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 50.2 mg of material which was purified byrecrystallization to give 45.1 mg (90%) ofN-desbenzoyl-N-(t-butoxycarbonyl)-2-desbenzoyl-2-(3,5-dimethylbenzoyl)-10-desacetoxytaxol.

[0163] m.p.198-200° C.; [α]²⁵ _(Na) −49.0° (c 0.965, CHCl₃).

[0164]¹H NMR (CDCl₃, 300 MHz) δ7.72 (s, 2H, benzoate, ortho), 7,37 (m,5H, aromatic), 7.23 (s, 1H, benzoate, para), 6.21 (m, 1H, H13), 5.64 (d,J=7.2 Hz, 1H, H2β), 5.45 (m, 1H, NH), 5.25 (m, 1H, H3′), 5.20 (d, J=1.8Hz, 1H, H10), 4.94 (dd, J=9.3, 1.2 Hz, 1H, H5), 4.61 (m, 1H, H2′), 4.32(d, J=8.1 Hz, 1H, H20α), 4.21 (m, 1H, H7), 4.16 (d, J=8.7 Hz, 1H, H20β),3.89 (d, J=7.2 Hz, 1H, H3), 3.39 (m, 1H, 2′OH), 2.58 (m, 1H, H6α), 2.38(s, 6H, dimethylbenzoate), 2.36 (s, 3H, 4Ac), 2.27 (m, 2H, H14), 1.88(m, 1H, H6β), 1.83 (s, 3H, Me18), 1.74 (s, 3H, Me19), 1.33 (s, 9H,t-butyl), 1.22 (s, 3H, Me17), 1.12 (s, 3H, Me16).

EXAMPLE 12

[0165] (74-2)

Preparation ofN-desbenzoyl-N-(t-butoxycarbonyl)-2-desbenzoyl-2-(3-hydroxybenzoyl)-10-desacetyltaxol

[0166] To a solution of2-desbenzoyl-2-(3-triethyl-silyloxybenzoyl)-7,10-(bis)-O-triethylsilyl-10-desacetylbaccatin III (54.1 mg, 0.060 mmol) in 0.5 mL of THF at −45° C. was addeddropwise 0.066 mL of a 1.00 M solution of LiN(SiMe₃)₂ in hexane. After0.5 h at −45° C., a solution ofcis-1-(t-butoxycarbonyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (90mg, 0.240 mmol) in 0.5 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before0.5 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 76.7 mg of amixture containing(2′R,3′S)-2′,7,10-tris(triethylsilyl)-N-debenzoyl-N-(t-butoxycarbonyl)-2-desbenzoyl-2-(3-triethyl-silyloxybenzoyl)-10-desacetyltaxol and a very small amount of the (2′S,3′R) isomer.

[0167] To a solution of 76.7 mg of the mixture obtained from theprevious reaction in 4 mL of acetonitrile and 0.19 mL of pyridine at 0°C. was added 0.52 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 49.4 mg of material which was purified byrecrystallization to give 43.4 mg (88%) ofN-desbenzoyl-N-(t-butoxycarbonyl)-2-desbenzoyl-2-(3-hydroxybenzoyl)-10-desacetyltaxol.

[0168] m.p.153-155° C.; [α]²⁵ _(Na) −45.0° (c 0.560, CHCl₃).

[0169]¹H NMR (CDCl₃, 300 MHz) δ7.36 (m, 9H, aromatic), 7.10 (m, 1H, OH),6.38 (m, 1H, H13), 5.60 (d, J=9.9 Hz, NH), 5.53 (d, J=7.5 Hz, 1H, H2β),5.37 (m, 1H, H3′), 5.18 (d, J=1.2 Hz, 1H, H10), 4.90 (dd, J=9.9, 2.4 Hz,1H, H5), 4.75 (m, 1H, H2′), 4.29 (d, J=8.4 Hz, 1H, H20α), 4.24 (m, 2H,H7, H20β), 3.93 (d, J=7.5 Hz, 1H, H3), 3.29 (m, 1H, 2′OH), 2.56 (m, 1H,H6α), 2.36 (s, 3H, 4Ac), 2.27 (m, 2H, H14), 1.91 (s, 3H, Me18), 1.85 (m,1H, H6β), 1.76 (s, 3H, Me19), 1.33 (s, 9H, t-butyl), 1.24 (s, 3H, Me17),1.08 (s, 3H, Me16).

EXAMPLE 13

[0170] Compounds 64-4, 65-1, 65-2, 65-3, 65-4, 66-1, 66-2, 68-1, 68-2,73-4, 74-1 and 74-2 of Examples 1-12 were evaluated in in vitrocytotoxicity activity against human colon carcinoma cells HCT-116.Cytotoxicity was assessed in HCT116 cells by XTT(2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazoliumhydroxide) assay (Scudiero et al, “Evaluation of a solubletetrazolium/formazan assay for cell growth and drug sensitivity inculture using human and other tumor cell lines”, Cancer Res.48:4827-4833, 1988). Cells were plated at 4000 cells/well in 96 wellmicrotiter plates and 24 hours later drugs were added and serialdiluted. The cells were incubated at 37° C. for 72 hours at which timethe tetrazolium dye, XTT, was added. A dehydrogenase enzyme in livecells reduces the XTT to a form that absorbs light at 450 nm which canbe quantitated spectrophotometrically. The greater the absorbance thegreater the number of live cells. The results are expressed as an IC₅₀which is the drug concentration required to inhibit cell proliferation(i.e. absorbance at 450 nm) to 50% of that of untreated control cells.

[0171] All compounds had an IC₅₀ less than 0.5 and all except compound65-4 (Example 5) had an IC₅₀ less than 0.1 indicating that they arecytotoxically active.

What I claim is:
 1. A taxane derivative having the formula

wherein X₁ is —OX₆, —SX₇, or —NX₈X₉; X₂ is hydrogen, alkyl, alkenyl,alkynyl, aryl, or heteroaryl; X₃ and X₄ are independently hydrogen,alkyl, alkenyl, alkynyl, aryl, or heteroaryl; X₅ is —COX₁₀, —COOX₁₀,—COSX₁₀, —CONX₈X₁₀, or —SO₂X₁₁; X₆ is hydrogen, alkyl, alkenyl, alkynyl,aryl, heteroaryl, hydroxy protecting group, or a functional group whichincreases the water solubility of the taxane derivative; X₇ is alkyl,alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group; X₈is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, orheterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl; X₉ is anamino protecting group; X₁₀ is alkyl, alkenyl, alkynyl, aryl,heteroaryl, or heterosubstituted alkyl, alkenyl alkynyl, aryl orheteroaryl; X₁₁ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OX₁₀, or—NX₈X₁₄; X₁₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;R₁ is hydrogen, hydroxy, protected hydroxy or together with R₁₄ forms acarbonate; R₂ is —OCOR₃₁; R_(2a) is hydrogen; R₄ is hydrogen, togetherwith R_(4a) forms an oxo, oxirane or methylene, or together with R_(5a)and the carbon atoms to which they are attached form an oxetane ring;R_(4a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano,hydroxy, —OCOR₃₀, or together with R₄ forms an oxo, oxirane ormethylene; R₅ is hydrogen or together with R_(5a) forms an oxo, R_(5a)is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R₅ formsan oxo, or together with R₄ and the carbon atoms to which they areattached form an oxetane ring; R₆ is hydrogen, alkyl, alkenyl, alkynyl,aryl, or heteroaryl, hydroxy, protected hydroxy or together with R_(6a)forms an oxo; R_(6a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, orheteroaryl, hydroxy, protected hydroxy or together with R₆ forms an oxo;R₇ is hydrogen or together with R_(7a) forms an oxo, R_(7a) is hydrogen,halogen, protected hydroxy, —OR₂₈, or together with R₇ forms an oxo; R₉is hydrogen or together with R_(9a) forms an oxo; R_(9a) is hydrogen,hydroxy, protected hydroxy, acyloxy, or together with R₉ forms an oxo;R₁₀ is hydrogen or together with R_(10a) forms an oxo, R_(10a) ishydrogen, —OCOR₂₉, hydroxy, or protected hydroxy, or together with R₁₀forms an oxo; R₁₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, hydroxy, protected hydroxy or together with R₁ forms acarbonate; R_(14a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, orheteroaryl; R₂₈ is hydrogen, acyl, hydroxy protecting group or afunctional group which increases the solubility of the taxanederivative; and R₂₉ and R₃₀ are independently hydrogen, alkyl, alkenyl,alkynyl, monocyclic aryl or monocyclic heteroaryl, and R₃₁ issubstituted phenyl.
 2. The taxane derivative of claim 1 wherein X₃₁ isselected from the group consisting of

and Z is alkyl, hydroxy, alkoxy, halogen, or trifluoromethyl.
 3. Thetaxane derivative of claim 2 wherein Z is methyl or methoxy.
 4. Thetaxane derivative of claim 1 wherein R_(9a) is hydrogen.
 5. The taxanederivative of claim 1 wherein R_(9a) is hydroxy.
 6. The taxanederivative of claim 1 wherein R_(9a) is acetoxy.
 7. The taxanederivative of claim 1 wherein R₁₄ and R_(14a) are hydrogen, R₁₀ ishydrogen, R_(10a) is hydroxy or acetoxy, R₉ and R_(9a) together form anoxo, R₇ is hydrogen, R_(7a) is hydroxy, R₅ is hydrogen, R_(5a) and R₄and the carbons to which they are attached form an oxetane ring, R_(4a)is acetoxy, R₁ is hydroxy, X₁ is —OH, X₂ is hydrogen, X₃ is phenyl, X₄is hydrogen, X₅ is —COX₁₀, X₁₀ is phenyl or t-butoxy and the taxane hasthe 2′R, 3′S configuration.
 8. The taxane derivative of claim 1 whereinR₁₄ and R_(14a) are hydrogen, R₁₀ is hydrogen, R_(10a) is hydroxy oracetoxy, R₉ and R_(9a) together form an oxo, R₇ is hydrogen, R_(7a) ishydroxy, R₅ is hydrogen, R_(5a) and R₄ and the carbons to which they areattached form an oxetane ring, R_(4a) is acetoxy, R₁ is hydroxy, X₁ is—OH, X₂ is hydrogen, X₃ is alkyl or alkenyl, X₄ is hydrogen, X₅ is—COX₁₀, X₁₀ is phenyl, tert-, iso- or n-butoxy, ethoxy, iso- orn-propoxy, cyclohexyloxy, allyloxy, crotyloxy, 1,3-diethoxy-2-propoxy,2-methoxyethoxy, amyloxy, neopentyloxy, PhCH₂O—, —NPh₂, —NHnPr, —NHPh,and —NHEt.
 9. A pharmaceutical composition which contains the taxanederivative of claim 1 and one or more pharmacologically acceptable,inert or physiologically active diluents or adjuvants.